PROJECT SUMMARY/ABSTRACT Widespread HPV vaccination could greatly reduce the burden of HPV-attributable cancers, but few U.S. adolescents receive HPV vaccine according to the recommended schedule. To address this problem, public health leaders have prioritized the goal of improving primary care providers? prescribing practices and vaccine delivery systems. An important resource in this effort is the CDC?s AFIX (Assessment, Feedback, Incentives, and eXchange) program. Implemented by state and regional health departments nationwide, AFIX offers an evidence-based approach to engaging providers in immunization quality improvement. However, little is known about how to most effectively capitalize on our national AFIX infrastructure to increase HPV vaccination. To address this gap, the proposed study seeks to evaluate three approaches for improving HPV vaccination in primary care. In the first approach, we will partner with 3 state health departments to harmonize their routine adolescent AFIX programs with CDC recommendations. In the second, we will train physician educators to deliver outreach and education to primary care physicians, remotely via webinar. In the third, we will combine these approaches into a multi-level intervention. To evaluate these approaches, we will conduct a 4-arm RCT, randomizing 120 clinics in each of 3 partner states (or 360 total) to receive: AFIX delivered by the state?s health department (AFIX); physician-to-physician engagement delivered remotely by a physician educator (P2P); both AFIX and P2P engagement (AFIX+P2P); or neither intervention (control). The overall goal of this trial is to compare the effectiveness and efficiency of the AFIX, P2P, and AFIX+P2P approaches. To evaluate effectiveness (Aim 1), we will assess a range of vaccination outcomes, including vaccination coverage changes for HPV vaccine initiation (?1 dose), between baseline and 12-month follow-up, for adolescents ages 11-12. We hypothesize that AFIX and P2P, whether delivered alone or in combination, will increase coverage compared to the control, but that coverage changes will be largest for clinics receiving AFIX+P2P. To assess efficiency (Aim 2), we will conduct a mixed-methods process evaluation, including a cost analysis, to assess factors including reach, delivery cost, and best practice adoption. We anticipate that the multi-level AFIX+P2P approach will reach fewer clinics and cost more per clinic to deliver, but will also result in greater adoption of best practices and lower cost per vaccine dose. To further explore efficiency (Aim 3), we will evaluate the impact of delivering AFIX and P2P ?booster? visits at 12- month follow-up. We hypothesize that booster visits will further improve HPV vaccination coverage. The proposed trial builds on the work of a long-standing and productive team of collaborators to create highly scalable solutions to the problem of HPV vaccine underuse. By establishing how and for whom AFIX and P2P are effective, this study seeks to increase options available to public health leaders for mobilizing resources to ensure that our nation?s youth are protected from HPV-attributable cancers.